Production of phenylglutaric acid



United States Patent O 2,824,120 PRODUCTION OF PHENYLGLUTARIC ACID 6Claims. ct. {60 -475) The preparation of tetrahydrozoline involves theheating of 1,2,3,4-tctr ahydro l-naphthoic acid or an ester thereof withethylenediamine according to techniques well known in the art for thepreparation of 2-su'bstituted imidazolines. The required1,2,3,4-tetrahydro-1- naphthoic acid'h'as been prepared by the chemicalreduction'of 1-naphthoic,acid with sodium and alcohol. However, thistype offa reduction is quite hazardous,

even on a large laboratory scale, and cannot be considered forcommercial production. It has not been possible to control the catalyticreduction of l-naphthoic acid with sufficient precision to make this apractical method for producing the 1,2,3,,4-tetrahydro compound.

alternative route to 1,2,3,4-tetrahydro-l-naphthoic acid lcnown in theart involves cyclization of u-phenylglutaric acid to1,2,3,4-tetrahydro-4-oxo-l-naphthoic acid followed by reduction of theketo group. This process is illustrated schematically below.

COzH CO H Heretofore, two factors have mitigated against the commercialapplication of this process. 'One is the lacli of a simple and ellicientmethod of preparinga-ph'enyh glutaricacid and the other is theunwieldiness'of known methods for the reduction step. The objectofthis111-, vention' is to provide a simple and economical process for theproduction of u-phenylglutaric acid. A copending application SerialNumber 540,339, filed October 13, 1955,is concerned with a new andimproved process for carrying out the reduction step. Suitable processesare known in the art for carrying out the cyclization step.

2,824,120 Patented Feb. 18, 1958 An example of one such method appearsat the end of this specification.

The valuable process of this invention for preparing a-phenylglutaricacid can be carried out in the two steps represented below.

In the above structural formulae, R and R are lower alkyl groups,straight 9r branched chained, having less than abduteight carbon atoms.Examples of such groups are the methyl, ethyl, butyl, isobutyl, amyl and2-ethylhexyl groups, etc. Higher alkyl groups areapplicable, but thelower alkyl compounds are preferred because 'they are readily available,and they are in general, more soluble, lower boiling, and convenient tohandle.

The unique' feature of this process stems from the discovery that underproperly controlled conditions, itis possible to effect the conjugateaddition of just one mole of the phenylacetic ester to the acrylic esterthus yielding a monoalkylation product. Previous processes for thepreparation of wphenylglutan'c acid involvethe conjugate addition of aphenylacetic ester or nitrile to acrylonitrile or the addition ofphenylacetonitrile to an acrylic ester. None has emplo'yedthe novelcombination of esters of the instant process. The combinations ofnitriles or nitriles and esters of the prior art processes haveallyielded dialkyla'tion products unless some meas tire was taken toblock one of the a-hydrogen atoms of the phenylacetic acid component.The fact that monoalkylation withoutr'esort to blocking groups can beobtained by the'useof controlled conditions and the unique combinationof 'esters of this invention is'the surprising and critical featnre ofthis process. Y i

In each of theprior art processes based on this type of a conjugateaddition step, at leastone" of the reactants has been a; nitrile and ineach case it has been necessary to'block one ofthe'whydrogen'atoms ofthe phenylacetic acid component. i This is illustrated in theequationsgiven below. Hydrolysis and decarboxylation of each of the productsshown yields o -phenylgl-utaric acid.

The process of the instant invention is considerably more convenientand'economical than related prior art processes' The instantprocess hasonly two steps as opposed to at least three for "priorart processes A,B, and C above, and higher overall yields are obtained. Thus the'processof the present invention is considerably more economical than the priorart methods. Economy is not (D) ano a i l C 2(COz )a CuHsCHaCOzOzHsCuHaCCOnCn 5 HO OnCzHs pyridine CHCHzCOaH OHOHZCOZH Here again a longerand more complicated process is involved. This process has the addeddisadvantage of including a hydrogenation step which requires the use ofspecialized equipment and catalysts which'mustbe either prepared orbought, and also recovered. The processof theinstant invention thereforeretains its advantages of economy and convenience over process D above.

Conjugate addition referred to above is a term known in the art which isused to describe the process of 1,4- additionacross a pair of conjugateddouble bonds followed by the:tautomeric rearrangement of the conjugateaddition intermediate to the 3,4-addition product that is isolated. Thisis illustrated below.

The conjugate addition of an activated carbon atom bearing at least onehydrogen atom to a 1,4-unsaturated system of the type referred to abovecontaining oxygen generally requires the presence of a catalyst foritssuccessful operation. This catalyst is referred to herein as a conjugateaddition catalyst. Suitable conjugate addition catalysts include basicsubstances of a variety of types. Both organic and inorganic bases havebeen used. Inorganic bases that are frequently applicable include thealkali metals, the alkali metal and alkaline earth oxides andhydroxides, and various alkali and alkaline earth hydrides such assodium hydride and calcium hydride. Organic bases include the loweralkali metal alkoxides, containing less than about eight carbon atoms,such as sodium methoxide, sodium ethoxide, and potassium t-butoxide,alkali. metal amides such as sodium amide, potassium amide, quaternaryammonium bases, such as trialkylammonium hydroxides and alkoxidesincluding such materials such as benzyltn'methylammonium hydroxide,benzyltrimethylammonium methoxide, choline, trimethylethylammoniumethoxide, etc. The term alkali metal amides used above is intended tomean the alkali metal derivatives of primary and secondary amines suchas sodium diethylamide, sodium methylamide, potassium piperidide, etc.as well as the simple amides derived from ammonia. Further materialsthat have been useful as conjugate addition catalysts include thestrongly basic ion exchange resins in the hydroxide or alkoxide formsuch as Dowex 1 and 2, Durolite A-40, A-4l, and A-42, IRA-400, IRA-401,and IRA-411. In general, such resins are polymers containingquaternaryammonium groups. For example, a copolymer of styrene and divinyl benzenewhich has been chloromethylated and treated with a tertiary amine toyield a polyquaternary ammonium chloride is one type that may beemployed. This can then be-converted into the hydroxide or alkoxide formin which form it is useful as a conjugate addition catalyst. Tosummarize, suitable catalysts include alkali .4 metals, and the oxides,hydroxides, lower alkoxides, amides and hydrides thereof; the alkalineearth metal oxides, hydroxides, and hydrides; and the quaternaryammonium bases such as the hydroxides, and lower alkoxides including thestrongly basic ion exchange resins which contain these groups. V

The reaction is preferably carried out by placing the ester ofphenylacetic acid and the conjugate addition catalyst in a flask andadding the acrylate ester to the mixture gradually with stirring'andcooling. The variables of the process include the choice and amount ofcatalyst, the proportions of reactants, and the conditions of time andtemperature employed. 'An inert solvent may be used but it is preferredto operate in the absence of a solvent. Inert solvents include polar andnon-polar organic liquids that will not react with the basic catalystemployed nor with the acrylic ester. Examples include all) certainalcohols, such as tertiary butyl alcohol; ethe rs such as diethyl ether,dibutyl ether, dioxane; and hydrocarbons suchas benzene, toluene,xylene, octane, etc. The bulk of the lower aliphatic primary andsecondary alkanols are unsatisfactory solvents due to the fact that theywill undergo conjugate addition to the acrylate. In general, thereaction rate is reduced considerably when a solvent is used.

Preferred conjugate addition catalysts include the alkali metalalkoxides although other materials of the types listed above may beused. From about 3 to 15 mole percent of catalyst is ordinarily used.The selection of a catalyst must be balanced with the other reactionvariables selected. Each has certain advantages and disadvantages. Forexample, potassium t-butoxide is an excellent catalyst because it isvery strongly basic and permits the use of low reaction temperatures andshort reaction times. These conditions favor the desired monoalkylation.However, potassium which is required in the preparation of this catalystis too hazardous to handle to be a practical material to employ on acommercial scale.

Sodium methoxide, ethoxide and other lower alkoxides have proven to bevery useful catalysts. Although they are not as active as potassiumt-butoxide and do not give such high yields and conversions as does thepotassium catalyst, they are less hazardous to use and have been foundto give adequate results.

The use of approximately equimolar amounts of the phenylacetic ester andacrylic ester is preferred in the process of this invention although insome instances, it is convenient to use an excess of one or the other tocounter-balance undesired side reactions. For example, the lower sodiumalkoxide catalysts react to some extent with the acrylate ester to giveconjugate addition products of the corresponding alcohols. Thus, anexcess of the acrylate is desirable and a somewhat larger proportion ofalkoxide catalyst is required. 7 A further side reaction that sometimesbecomes troublesome at the higher temperatures in the useful range ofthis process is polymerization of the acrylate ester. This can beminimized by the addition of a basic polymerization inhibitor such asone of the aromatic amines including dimethylaniline, diphenylamine,di-B-naphthyl-p-phenylenediamine etc., to the reaction mixture. Otherpolymerization inhibitors are also useful. Ordinarily polymerization ofthe acrylate ester is not a problem.

Side reactions involving the phenylacetic ester are also possibleresulting in loss of this reactant. One such reaction involvescondensation of two molecules of the ester with one another to give adi'substituted acetoacetic ester. This material is readilydecarboxylated yielding dibenzyl ketone as a contaminant. Thus, in someinstances an excess of the phenylacetic ester may be desirable. Ingeneral, useful mixtures for carrying out this reaction are thosecomprising equimolar quantities of the two 'esters as well as thosecomprising up to about a 50% excess of one or the other of them. Inother words from two thirds to one and a half moles of the phenylaceticester per mole of acrylic ester are preferably employed. For example,use of sodium methoxide as the catalyst and ethyl phenylacetate andmethyl acrylate as the reactants, a temperature of 30 C. for 2.0 hourshas been found to be a suitable combination of time and temperature.This set of conditions results in a 67% yield of methyl ethyla-phenylglutarate. Similarly, with the useof pota'ssium tertiarybutoxide, yields of 85 to 95% were obtained operating at temperatures of--25 to +5 More weakly basic catalysts such as sodium hydroxide orpotassium hydroxide accordingly requireua combination of a higherreaction temperature and longer reaction time. It has been found thatthe useful temperature range for carrying out this process issubstantially between -40 and +60 C. j

After completion of the reaction period, the catalyst is neutralized bythe addition of an equivalent quantity of acid. Organic acids may beused as well as the inorganic mineral acids. In fact, it is preferred touse acetic acid or other weak anhydrous acid since the presence ofstrong aqueous acids favors hydrolysis of the ester. The resultinginsoluble salts are preferably removed from the reaction mixture priorto distillation of the product since their presence leads to caking anduneven ebullition which complicates the distillation step. Salt removalmay be accomplished by a variety of means such as filtering,centrifuging, or solvent extraction. In a preferred emboditions ofchloroform andthe combined chloroform layers dried and the solventdistilled. The" remaining liquid was the product methyl ethyla-phenylglutarate; It was fractionated through alS centimeterhelices-packed colurnn'. It had a boiling point of 148-150 C. and D=1.4944. It weig'hed 2.53 kg. This represented a 67% yield of thedesired a-phenyl glutaric ester.

EXAMPLE II In order to illustrate the effect of the variables of time,temperature, and amounts of reactantsou the product produced, a seriesof experiments was carried out in a fashion similar to that describedabove in Example I.

Theresults of these runs are tabulated below. The percentage figure inthe column headed Conversion is the percent of product produced comparedto the theoretical weight of product expected on the basis, of startingmaterial charged. The yield figure in the last column head Comparativeefiect of reaction variables on yield and conversion OGHEOHIOOSR CH==CHCOiR Catalyst Time Temp Percent Yield (hours) C.) Oonver- (Percent) RMoles R Moles Formula AD(J01)]JJt sion 0. 5 CH3 0. 5 N 80CH3-- 2 4 20 6677 0. 6 acrylonitrile 0. 5 N aOCH; 2 4 20 52 61 0. 6 CH3 0. 5 NaOCHs 2 220 28 50 1. 0 1. 0 NaOCHs 4 4 20 70 85 0. 1 0. 1 KO-t-C4Hs. 0. 4 3 5 8084 O. 1 0. 1 KO-t-C4Hg.- 0. 4 7 5 79 87 0. 1 0. 1 KO-t-C4H9. 0.4 6 25 8690 0.5 0. 5 NaOCHa 2 4 5 23 41 ment of the invention, solvent extractionwith the system EXAMPLE III chloroform-water is employed.

The following examples are given to illustrate specific embodiments ofthis invention and are not to be considered as limiting it in any way.In fact, resort may be had to many variations without departing from thespirit and scope thereof. Examples are also given to illustrate themanner in which the a-phenylglutaric acid produced by the valuableprocess of this invention may be converted tol,2,3,4-tetrahydro-4-oxo-l-naphthoic acid.

EXAMPLE 1 Ethyl phenylacetate, 2.46 kg. (15 moles) and 100 g. of sodiummethoxide was placed in a 5 l. flask equipped with stirrer, thermometer,and dropping funnel. The reflux condenser was capped with a soda-limetube and the reaction mixture was protected from the atmosphere with drynitrogen gas throughout. The mixture was then agitated and 1.29 kg. (15moles) of methyl acrylate was added during 1.5 hours. The temperaturewas maintained at i5 C. by means of ice cooling. It was noticed in someruns that the reaction ceased to be strongly exothermic during theaddition. In these cases, the addition of a further quantity of sodiummethoxide was necessary. Stirring was continued for 30 minutes at theabove temperature after all of the methyl acrylate had been added. Thereaction was then quenched with 120 g. of glacial acetic acid andtreated with 1 1. of water, 1 l. of chloroform and 75 ml. ofconcentrated sulfuric acid to facilitate the separation of the layers.The two layers were separated and the chloroform layer washed with a1 1. portion of water. The combined aqueous layers were then extractedwith two 500 ml. por

A solution of 240 g. of sodium hydroxide in 2.8 l. of water was preparedand 600 g. (2.4 moles) of the ester from Example I was added to it. Thismixture was refluxed with vigorous stirring for three hours. The cooledreaction mixture was then extracted with 500 ml. of chloroform and theaqueous layer acidified with 200 ml. of concentrated sulfuric acid. Theu-phenylglutaric acid separated and was collected by extracting withseveral portions of chloroform. The combined extracts were dried and thesolvent removed leaving the ot-phenylglutaric acid.

EXAMPLE IV The u-phenylglutaric acid obtained from arm of the scaledescribed in Example III was treated with 1.2 l. of concentratedsulfuric acid at such a rate that the internal temperature remainedabove C. This required about 15 minutes. The reaction mixture wasmaintained at 98-100" C. for an additional 15 minutes and allowed tocool to room temperature. This solution was then added during about 45minutes to 5 l. of cold water contained in a 12 1. flask. Efi'icientstirring was continued throughout the addition and the aqueoussuspension was seeded with an authentic sample ofl,2,3,4-tetrahydro-4-oxo-lnaphthoic acid after about 100 ml. of theabove sulfuric acid solution had been added. The temperature wasmaintained at 2530 C. during this process by means of external cooling.The product was collected on a filter after a digestion period of onehour and the keto acid was washed with water until the pH of the washesexceeded 1.5. Eight 100 ml. portions of cold water were required. Theproduct was air dried at 5560 C.

It weighed 271 g. and had a melting point of 94-195.-5 C. The neutralequivalent of this product was -1,9 1 which compares favorably with thecalculated value of 190 for 4-keto-1,2,3,4-tetrahydro-l-naphthoic acid.A second crop of the keto naphthoic acid can be obtained from thefiltrate by solvent extraction with chloroform .and recrystallization ofthe so-obtained material from toluene. This increases the total yield toabout 300 g. which is 77% theoretical based on the methyl ethyla-phenylglutarate charged to the hydrolysis step.

What is claimed is: V

1. The process for preparing a lower alkyl diester of a-phenylglutaricacid which comprises the steps of mixing a lower alkyl ester ofphenylacetic acid with 315 mole percent of a 1,4- addition catalyst,adding thereto from /2, to 1 moles of a lower alkyl esterofacrylic acidper mole of lower alkyl ester of phenylacetic acid at a temperaturesubstantially in the range of 40? C. to +60 C., and recoveringuphenylglutaric diester.

2. The process of claim 1 wherein the catalyst is neutralized prior torecovery of the diester.

3. The process of claim 1 wherein the diester is recovered by solventextraction.

4. The process for preparing a-phenylglutaric acid which comprises thesteps of mixing a lower alkyl ester of phenylacetic acid with 3-15 molepercent of a 1,4-addition catalyst, adding thereto from /3 to 1 /2 molesof a lower alkyl ester of acrylic acid per mole of lower alkyl ester ofphenylacetic acid at a temperature substantially in the range of -40 C.to +60 C., recovering a-phenylglutaric diester, and hydrolizingrecovered diester.

5. The process of claim 4 wherein hydrolysis of the diester is carriedout in an aqueous alkaline solution and a-phenylglutaric acid isrecovered therefrom.

6. The process of claim 5 wherein recovery of a-phenylglutaric acidcomprises acidification and solvent extraction of hydrolysis mixture.

ReferencesCited in the file of this patent Hickinbottom

4. THE PROCESS FOR PREPARING A-PHENYLGLUTARIC ACID WHICH COMPRISES THESTEPS OF MIXING A LOWER ALKYL ESTER OF PHENYLACETIC ACID WITH 3-15 MOLEPERCENT OF A 1,4-ADDITION CATALYST, ADDING THERETO FROM 2/3 TO 1 1/2MOLES OF A LOWER ALKYL ESTER OF ACRYLIC ACID PER MOLE OF LOWER ALKYLESTER OF PHENYLACETIC ACID AT A TEMPERATURE SUBSTANTIALLY IN THE RANGEOF -40*C. TO +60*C., RECOVERING A-PHENYLGLUTARIC DIESTER, ANDHYDROLIZING RECOVERED DIESTER.